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Monoclonal antibodies

Anticancer therapy Weihua Wu

play a role in immediate hypersensitive and denfensive for parasite . all clones of a single parent cell. Isotypes According to differences in their heavy chain constant domains. IgG: IgG1 (66%). IgD. and IgE. Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by one type of immune cell. IgG2 (23%).What is antibodies An antibody is a protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Polyclonal antibodies are antibodies that are derived from different cell lines. blood and tissue liquid. IgA. immunoglobulins are grouped into five classes. Each antibody recognizes a specific antigen unique to its target. stomach and intestines IgM: normally pentamer. IgG3 (7%) and IgG4 (4%) . IgA:IgA1 (90%) and IgA2 (10%). ocassionally hexamer. IgM. multiple immunoglobins linked with disulfide bonds IgD:1% of proteins in the plasma membranes of B-lymphocytes. function unknown IgE: on the surface of plasma membrane of mast cells. or isotypes: IgG.

ac.The structure of antibodies  http://www.html

      1975 Kohler and Milstein provided the most outstanding proof of the clonal selection theory by fusion of normal and malignant cells 1990 Milstein produced the first monoclonal antibodies.History of Mab development  1890 Von Behring and kitasato discovered the serum of vaccinated persons contained certain substances. . Porter isolated fragment of antigen binding (Fab) and fragment crystalline (Fc) from rabbit y-globulin. 1964 Littlefield developed a way to isolate hybrid cells from 2 parent cell lines using the hypoxanthine-aminopterin-thymidine (HAT) selection media. termed antibodies 1900 Ehrlich proposed the “ side-chain theory” 1955 Jerne postulated natural selection theory. Frank Macfarlane Burnet expended. Almost the same time.

Clinical efficacy compromised by HAMA(human anti murine antibody) response. Chimeric mAbs: chimers combine the human constant regions with the intact rodent variable regions. Affinity and specificity unchanged. Also cause human antichimeric antibody response (30% murine resource) C. Humanized mAbs: contained only the CDRs of the rodent variable region grafted onto human variable region framework . generated using conventional hydrioma technology. which lead to allergic or immune complex herpersensitivities. B.The types of mAb designed A. Murin source mAbs: rodent mAbs with excellent affinities and specificities.

Nature of cytotoxin Lack of in vivo selectivity The mechanism of anti-proliferation on cells cycle. . rather than specific toxicity directed towards particular cancer cell Host toxixity: treatment discontinued. such as no appetites. C. lose hair B. most of them had bad side-effects.Chemotherapy Shortcomings: A. omit. D.

mAbs was modified for delivery of a toxin. A. or interfering with a key function. Such as inducing cancer cell apoptosis.Monoclonal antibodies for cancer treatment Three mechanisms that could be responsible for the cancer treatment. inhibiting growth. it is also possible to design bispecific antibodies that can bind with their Fab regions both to target antigen and to a conjugate or effector cell . C. cytokine or other active conjugates. B. mAbs act directely when binding to a cancer specific antigens and induce immunological response to cancer cells. radioisotope.

1:118-129 . ADCC. Nat Rev Cancer 2001. MAb. single-chain Fv fragment. complement dependent cytotoxicity. antibody dependent cell-mediated cytotoxicity. CDC. monoclonal antibody. Carter P: Improving the efficacy of antibody-based cancer therapies. antibody directed enzyme prodrug therapy. scFv.mAbs treatment for cancer cells ADEPT.

mAbs target growth factor receptors to exert a direct effect on the growth and survival of the cancer cells by antagonizing ligand-receptor signaling. 2. mAbs can target to cell surface antigens and directly elicit apoptotic signaling. 9097-9106 . etal. Oncogene(2003) 22. Dale L Ludwig.Strategy of a direct or in direct induction of apoptosis in targeted cancer cells 1.

Immunol. 2005.9 Stamatis-Nick C. 2005 . The first approved mAbs was OKT-3. which is a murine IgGa2 protein to deplete T cells in patients with acute rejection of renal allotransplant. No. Oct. etal. J Allergy Clin. 18 mAbs were approved by FDA. which were applied in the treatment of organ transplant. HAMA response Jancie. Hematopoietic malignancies and psoriasis.Until Feb 28. Sep. M Recheit. Cancer. Asthma. 23.Vol. 2005. Nature biotechnology.

The phage expressing an antigen-bonding domain specific for a particular antigen to screen the mAbs.mAbs development 1.CA) 3. Transgenic plants: transgenic tobacco plants to produce IgA. Transgenic animals: transgenic mouse to make humanized IgG. (Abgenix. Phage display library: construction of VH and VL gene libaries and expression of them on a filamentous bacterophage. 2. .

According to the different cell culture methods. . it can calisifed into four fields 1. 4. Membrane binded cell culture process Microcarrier cell culture process Suspended cell culture process 3. Robottle cell culture process. The several process had been developed at large scale. 2.Conventional production of mAbs The hybridoma technology: spleen cells from immunized mice are fused with the murine myeloma cells.

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